Our Program focuses on the determinants of cardiac rhythm and arrhythmias in the young. The unifying hypothesis is that the expression of cardiac electrical activity in the young heart is influenced by the autonomic nervous system and determined by ion channels in ways that are unique, and that require our in-depth understanding if we are to advance our capability to prevent and treat disorders of the heart beat. Our previous approach to research was multifaceted, incorporating electrophysiological, pharmacological, biophysical, biochemical and cell culture continues in the renewal to which the perspective of molecular biology has been added and incorporated The research concentrates on mechanisms for normal impulse initiation and the mechanisms whereby abnormal impulse initiation and abnormal repolarization can be facilitated by anomalies of sympathetic innervation, thereby leading to lethal arrhythmias. A key aspect of the work is the relationship of sympathetic innervation to the evolution of ion channel function and signal transduction processes, including both the beta and alpha-adrenergic pathways. The relationship of normal function to that in sympathectomized animals and to that in an inherited model of partial failure of sympathetic innervation and lethal arrhythmias is stressed. The latter model is of particular interest because it appears related to catecholamine-and to exercise-dependent ventricular tachycardias in human subjects. The five Projects in the Program stress the study of electrophysiologic properties and autonomic modulation in intact animals and isolated tissues, ionic and molecular determinants of repolarization studied in single myocytes; ionic and molecular determinants of repolarization studied in single myocytes and in nerves and myocytes in tissue culture; and receptor-effector coupling mechanisms. Two Cores provide administrative and a variety of support services; One Core provides cell disaggregation and tissue culture. The significance of these studies is that while geared to the young age group as a unique population in which rhythm and arrhythmias differ in genesis and autonomic modulation from the adult, the information gained from these studies derives from and is readily referable to advancement of our understanding of rhythm an arrhythmias across all ages. Using the information obtained we will not only advance our understanding of the mechanisms responsible for normal rhythm and arrhythmias, but can design and seek new means for prevention and treatment of arrhythmias.